Fumagillol derivative and the medical use thereof

ABSTRACT

The disclosure relates to a fumagillol compound which can be usefully used not only as an angiogenesis inhibiting agent showing a superior angiogenesis inhibitory effect with less toxicity, but also as a cancer metastasis inhibitor and a therapeutic agent against cancer and other various inflammatory diseases such as rheumatic disease, psoriasis, etc., and diabetic retinopathy related to angiogenesis, and also a method for preparing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of prior application Ser. No.11/494,026 filed on Jul. 26, 2006 and incorporated herein by referencein its entirety, which is a divisional of U.S. Pat. No. 7,087,768 issuedon Aug. 8, 2006 and incorporated herein by reference in its entirety,which claimed priority of Korean Application No. 2001-60017 filed onSep. 27, 2001 and Korean Application No. 2002-29915 filed on May 29,2002.

TECHNICAL FIELD

The present invention is directed to a fumagillol derivative or apharmaceutically acceptable salt thereof, showing excellent angiogenesisinhibitory effect, with low toxicity; a preparation method thereof; anda medical use thereof.

PRIOR ART

Angiogenesis is a phenomenon of forming new vessels at the capillarylevel by a series of processes, such as proliferation, infiltration andtransfer, and interactions of vein endothelial cells. This phenomenon isconsidered to be not only a normal physiological process but also apathological process of various diseases. Angiogenesis, properlycontrolled by various physiological substances, is an importantphysiological process, which is seen upon healing of wounded parts orformation of uterine endothelia after birth or menstruation.

However, in the uncontrolled state, angiogenesis that excessivelygenerates novel capillary vessels is regarded as a pathologicalcondition. Such angiogenesis is known to be closely associated withgrowth and metastasis of solid cancers, diabetic retinopathy, rheumaticarthritis and psoriasis [Billington, D. C. Drug Design and Discovery,(1991), 8, 3.].

Much research on inhibition of such angiogenesis regarded as apathological condition has been performed. Judah Folkman of the MedicalCollege of Harvard University suggested a new concept of treating solidcancer by inhibiting angiogenesis in 1971 [J. Folkman, New Engl. Med.,185 (1971), 1182-1185]. In other words, an angiogenesis inhibitory agentis responsible for decrease or inhibition of growth of solid cancers,resulting in blocking metastasis of solid cancer. Such an angiogenesisinhibitory agent has a useful therapeutic effect for other inflammatorydiseases, such as diabetic retinopathy, rheumatoid arthritis, psoriasis,etc, in addition to solid cancers.

Compounds inhibiting angiogenesis have been developed through manyefforts up to the present, and so various compounds are known as novelangiogenesis inhibitory agents.

In this regard, European Pat. Nos. 0 354 787, 0 357 061 and 0 415 294,and Japanese Pat. No. JP-AO1-233275 disclose fumagillol derivatives.

Further, it has been reported that 6-amino-6-deoxyfumagillol [Chem.Pharm. Bull., 40, 575-579 (1992)], 6-O-acyl, 6-O-sulfonyl, 6-O-alkyl,6-O-(N-substituted carbamoyl)fumagillol [Chem. Pharm. Bull., 40, 96-101(1992)] have angiogenesis inhibitory functions.

However, there is required a continuous development of angiogenesisinhibitory agents exhibiting excellent angiogenesis inhibitory effectwith less toxicity, and having novel chemical structure.

DISCLOSURE OF THE INVENTION

Leading to the present invention, the intensive and thorough researchinto novel compounds having high inhibitory effect on angiogenesis,carried out by the present inventors, resulted in the finding that ananiline derivative having various substituents can be introduced to aknown fumagillol, whereby a compound of the formula I, which hasangiogenesis inhibitory effect and low toxicity, can be prepared.

It is therefore an object of the present invention to provide afumagillol derivative or a pharmaceutically acceptable salt thereof,exhibiting excellent angiogenesis inhibitory effect.

It is another object of the present invention to provide a method ofpreparing such a fumagillol derivative.

It is a further object of the present invention to provide apharmaceutical composition for angiogenesis inhibition, usable as anangiogenesis inhibitor, comprising a fumagillol derivative or apharmaceutically acceptable salt thereof as a useful ingredient.

The above objects are achieved by providing the fumagillol derivative orthe pharmaceutically acceptable salt thereof of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view showing the decrease of the tumor size of mice treatedwith the compounds of Ex. 1, Ex. 11, Ex. 63 and Ex. 64 according to thepresent invention compared with that of mice treated with vehicle alone.

FIG. 2 is a series of photographs showing the size of tumor cells inxenografted nude mice treated with buffer alone or treated with Ex. 1and Ex. 64 according to the present invention.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention provides a fumagillol derivative represented bythe following general formula I, or a pharmaceutically acceptable saltthereof:

(wherein,

X is —OH and Y is halogen, or X and Y are linked together to form anoxirane ring,

B represents —(C═O)— or —CH₂—,

R₁ represents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄thioalkyl; acetamido; acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino;C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; C₁-C₄alkyloxycarboxylic acid, or

in which R₂, R₃, R₄, R₅ and R₆, which are the same or different, eachrepresents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄ thioalkyl;acetamido; acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino;C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; or C₁-C₄alkyloxycarboxylic acid; or, R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ andR₆, are linked together to form a C₁-C₃ alkylene dioxy ring, and

Z₁, Z₂, Z₃, Z₄ and Z₅ each represent carbon or nitrogen).

Preferably, X and Y are linked together to form the oxyran ring, and Bis —(C═O)—,

R₁ is hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido; acetoxy;C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino; C₁-C₆ alkylamino;C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; C₁-C₄ alkyloxycarboxylic acid,or

R₂, R₃, R₄, R₅ and R₆, which are the same or different, each representshydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido; acetoxy; C₁-C₆alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl;C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄dialkylaminoalkoxy; amino; C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄hydroxyalkyl; or C₁-C₄ alkyloxycarboxylic acid, or

R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ and R₆ are linked together toform the C₁-C₃ alkylene dioxy ring, and

Z₁, Z₂, Z₃, Z₄ and Z₅ each represent carbon or nitrogen.

More preferably, R₁ is selected from the group consisting of hydrogen;hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy;propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy;dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro;acetoxy; trifluoromethyl; and hydroxyethoxy,

R₂, R₃, R₄, R₅ and R₆ is independently selected from the groupconsisting of hydrogen; hydroxy; methyl; chlorine; methoxy;methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino;dimethylaminomethyl; methylpropoxy; dimethylethoxy;3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy;dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy;trifluoromethyl; and hydroxyethoxy, and

Z₁, Z₂, Z₃ Z₄ and Z₅ each represent carbon or nitrogen.

The fumagillol derivative of the above formula I has at least 6 chiralcenters, as represented by the following formula, and in the scope ofthe present invention, each optical isomer or mixtures thereof isincluded:

In addition, the present invention further comprises 6-O-(chloro)acetylfumagillol as an intermediate represented by the formula II, for use inpreparation of the fumagillol derivative of the formula I:

Among the compounds of the formula I, preferred are:

-   1) 6-O-(4-methoxyaniline)acetyl fumagillol;-   2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;-   3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;-   4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;-   5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;-   6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;-   7) 6-O-(4-allyloxyaniline)acetyl fumagillol;-   8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;-   9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;-   10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl    fumagillol;-   11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;-   12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;-   13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;-   14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;-   15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;-   16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;-   17) 6-O-(4-propyloxyaniline)acetyl fumagillol;-   18) 6-O-(aniline)acetyl fumagillol;-   19) 6-O-(4-chloroaniline)acetyl fumagillol;-   20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;-   21) 6-O-(4-hydroxyaniline)acetyl fumagillol;-   22) 6-O-(4-aminoaniline)acetyl fumagillol;-   23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;-   24) 6-O-(4-nitroaniline)acetyl fumagillol;-   25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;-   26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;-   27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;-   28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;-   29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;-   30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;-   31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;-   32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;-   33) 6-O-(4-acetoxy aniline)acetyl fumagillol;-   34) 6-O-(4-cyanoaniline)acetyl fumagillol;-   35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;-   36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;-   37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;-   38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;-   39)    4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;-   40)    4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;-   41) 6-O-(ethylamino)acetyl fumagillol;-   42) 6-O-(isopropyl amino)acetyl fumagillol;-   43) 6-O-(1-propyl amino)acetyl fumagillol;-   44) 6-O-(1-butyl amino)acetyl fumagillol;-   45) 6-O-(sec-butyl amino)acetyl fumagillol;-   46) 6-O-(2-methyl-butylamino)acetyl fumagillol;-   47) 6-O-(t-butyl amino)acetyl fumagillol;-   48) 6-O-(pentyl amino)acetyl fumagillol;-   49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;-   50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;-   51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;-   52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;-   53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;-   54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;-   55) 6-O-(3-methylbutylamino)acetyl fumagillol;-   56) 6-O-(2-methylallylamino)acetyl fumagillol;-   57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;-   58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;-   59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;-   60) 6-O-(prop-2-enylamino)acetyl fumagillol;-   61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;-   62) 6-O-(chloroethynylamino)acetyl fumagillol;-   63) 6-O-(cyclopropylamino)acetyl fumagillol;-   64) 6-O-(cyclobutylamino)acetyl fumagillol;-   65) 6-O-(cyclopentylamino)acetyl fumagillol;-   66) 6-O-(cyclohexylamino)acetyl fumagillol;-   67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;-   68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;-   69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;-   70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;-   71) 6-O-(2-oxo-propylamine)acetyl fumagillol;-   72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;-   73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;-   74) 6-O-(alanine-methylesteramino)acetyl fumagillol;-   75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;-   76) 6-O-(allylglycine-methylester)acetyl fumagillol;-   77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;-   78)    4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;-   79)    4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    and-   80) 6-O-(chloro)acetyl fumagillol.

Among the compounds of the formula I, most preferred are:

-   1) 6-O-(4-methoxyaniline)acetyl fumagillol;-   2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;-   3) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;-   4) 6-O-(cyclopropylamino)acetyl fumagillol;-   5) 6-O-(cyclobutylamino)acetyl fumagillol;-   6)    4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    and-   7)    4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.

Structural formulas of the above compounds are shown in Tables 1a to 1d,below. TABLE 1a

Ex. 1

Ex. 2

Ex. 3

Ex. 4

Ex. 5

Ex. 6

Ex. 7

Ex. 8

Ex. 9

Ex. 10

Ex. 11

Ex. 12

Ex. 13

Ex. 14

Ex. 15

Ex. 16

Ex. 17

Ex. 18

Ex. 19

Ex. 20

TABLE 1b

Ex. 21

Ex. 22

Ex. 23

Ex. 24

Ex. 25

Ex. 26

Ex. 27

Ex. 28

Ex. 29

Ex. 30

Ex. 31

Ex. 32

Ex. 33

Ex. 34

Ex. 35

Ex. 36

Ex. 37

Ex. 38

Ex. 39

Ex. 40

TABLE 1c

Ex. 41

Ex. 42

Ex. 43

Ex. 44

Ex. 45

Ex. 46

Ex. 47

Ex. 48

Ex. 49

Ex. 50

Ex. 51

Ex. 52

Ex. 53

Ex. 54

Ex. 55

Ex. 56

Ex. 57

Ex. 58

Ex. 59

Ex. 60

TABLE 1d

Ex. 61

Ex. 62

Ex. 63

Ex. 64

Ex. 65

Ex. 66

Ex. 67

Ex. 68

Ex. 69

Ex. 70

Ex. 71

Ex. 72

Ex. 73

Ex. 74

Ex. 75

Ex. 76

Ex. 77

Ex. 78

Ex. 79

Inter- medi- ate

The fumagillol derivative of the present invention, represented by theformula I, may be used in a form of a pharmaceutically acceptable salt.In particular, an acid addition salt formed by a pharmaceuticallyacceptable free acid is usefully used. As the free acid, an inorganicacid and an organic acid may be used. Examples of the inorganic acidinclude hydrochloric acid, bromic acid, sulfuric acid and phosphoricacid. The organic acid is exemplified by citric acid, acetic acid,lactic acid, tartaric acid, maleic acid, umaric acid, gluconic acid,methansulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonicacid, galacturonic acid, embonic acid, glutamic acid or aspartic acid.

Additionally, the present invention provides a method of preparing anacetyl fumagillol derivative and a pharmaceutically acceptable saltthereof, as represented by the following Reaction Scheme 1.

Specifically, the preparation method of the fumagillol derivativecompound in which B is —(C═O)—, comprises the steps of:

(a) acylating a compound of the formula 2 with α-halocarboxylic acidderivative in the presence of a base, to give a compound of the formula3; and

(b) reacting the compound of the formula 3 with an amine compound of theformula 4, to prepare the fumagillol derivative represented by theformula 1a via substitution.

(wherein, R₁ is as defined above)

In the present invention, the prepared compound of the formula 1a istreated with an acid, or reacted with a salt in the presence of an acidcatalyst, to perform an oxirane ring-opening reaction, thereby yieldingthe fumagillol derivative represented by the formula 1b, as shown in thefollowing Reaction Scheme 2:

(wherein, R₁, X and Y are as defined above)

Below, a description will be given of each step.

(1) Acylation Step

The compound of the formula 2 as a starting material is acylated withα-halocarboxylic acid derivative having high reactivity, in the presenceof the base, to give the compound of the formula 3, as seen in thefollowing Reaction Scheme 3.

Specifically, the compound of the formula III is a fumagillol, which isa hydrolyzed product of fumagillin produced by microbial fermentation[Tarbell, D, S. et. al., J. Am. Chem, Soc., 83, 3096 (1961)]81).

The above α-halocarboxylic acid derivative is selected from amongchloroacetyl chloride, chloroacetyl bromide, chloroacetyl iodide, andchloroacetyl fluoride, and used in the amount of 1-5 equivalents,preferably in 1-1.5 equivalents, based on the compound of the formula 2.

As for the base, an acid anhydride, a mixed anhydride or an acidchloride may be commonly used, and preferably, tertiary amines, such astriethylamine, diisopropylethyl amine, pyridine, dimethylamino pyridine,etc., are used in the amount of 1-10 equivalents. More preferably, 1-3equivalents of triethylamine, or dimethylaminopyridine is used.

The solvent used for acylation is selected from the group consisting ofdimethylformamide, dichloromethane, chloroform, diethylether,tetrahydrofuran, dioxane, acetonitrile, benzene and toluene. Preferably,dimethylformamide, dichloromethane or tetrahydrofuran is used.

As such, acylation is carried out at 0-50° C., preferably at 20-50° C.

2) Halogen-Amine Substitution Step

The compound of the formula 0.3, obtained from the previous acylationstep, is reacted with the compound of the formula 4 as the aminederivative, to yield the compound of the formula 1a having a substitutedamine compound, as seen in the following Reaction Scheme 4.

(wherein, R₁ is as defined above)

The aromatic compound of the formula 4, used in the above substitutionreaction, is used in the amount of 1-10 equivalents, preferably 1-3equivalents, based on the compound of the formula 3.

As for the amine compound, aliphatic or aromatic amine compound can beused. Such derivatives are specifically stated in the examples of thepresent invention.

The solvent used in this substitution reaction is selected from thegroup consisting of dimethylformamide, dichloromethane, chloroform,diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene andtoluene. It is preferred that dimethylformamide, dichloromethane ortetrahydrofuran is used.

The substitution reaction is performed at 0-100° C., preferably at20-50° C.

3) Oxirane Ring-Opening Step

The compound of the formula 1a, resulting from the above step, istreated with the acid, or reacted with the salt in the presence of theacid catalyst, to perform the oxirane ring-opening reaction, therebyyielding the fumagillol derivative represented by the formula 1b, as inthe following Reaction Scheme 5.

(wherein, R₁, X and Y₄ are as defined above)

Examples of the acid used in the ring-opening reaction includehydrochloric acid, bromic acid or iodic acid. The acid usable as thecatalyst comprises acetic acid, sulfuric acid, para-toluene sulfonicacid, hydrochloric acid, phosphoric acid or nitric acid. Of the acidcatalysts, acetic acid or hydrochloric acid is preferably used.

The salt used in this reaction is selected from the group consisting ofbromolithium, chlorolithium, sodium chloride, potassium chloride,potassium bromide, sodium bromide, potassium iodide, sodium iodide andlithium iodide. Preferably, chlorolithium, bromolithium, lithium iodideor sodium hydrogen carbonate.

Meanwhile, the preparation method of the compound in which B is —CH₂— isspecifically shown in the following Reaction Scheme 6.

Further, the present invention provides a pharmaceutical composition forangiogenesis inhibition, comprising the fumagillol derivative of theformula I or a pharmaceutically acceptable salt thereof as an effectiveingredient.

In order to investigate activity of the fumagillol derivative on cellgrowth, proliferation inhibition activity was measured using HUVECs(human umbilical vein endothelial cells). As the result, it was foundthat the inventive fumagillol derivative has superior growth inhibitioneffect, up to 2000 times greater than TNP-470, a conventionalangiogenesis inhibitory agent.

Therefore, it is expected that the fumagillol derivative of the formulaI can strongly inhibit proliferation of vein endothelial cells, thushaving excellent angiogenesis inhibitory effect. Such a fumagillolderivative can be usefully used for decreasing and inhibiting growth andmetastasis of cancer as well as treating other various inflammatorydiseases, including diabetic retinopathy, rheumatic arthritis andpsoriasis. Hence, the fumagillol derivative is usable as a cancermetastasis inhibitor, or a therapeutic agent against cancer, rheumaticarthritis, psoriasis and diabetic retinopathy.

With a view to evaluating general toxicity of the compound of theformula I according to the present invention, experiments on acutetoxicity were carried out using mice. As a result, it was found that thehalf lethal dose (LD₅₀) of each compound upon single oral administrationwas not less than 2 g/kg, whereby the compound was evaluated as a verysafe compound.

The compound of the formula I according to the present invention may beformulated, upon clinical administration, as a pharmaceutical solid,semi-solid or liquid type formulation which is suitable for oral orparenteral administration by blending this compound with apharmaceutically acceptable inert carrier.

The pharmaceutical composition of the present invention is formulatedinto dosage form for oral administration, for instance, tablet, troches,lozenge, water- or oil-soluble suspension, prepared powder or grain,emulsion, hard or soft capsule, syrup or elixir. For formulation of thetablet and capsule form, used are binders such as lactose, sacharose,sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; vehiclessuch as dicalcium phosphate; disintegrating agents, such as corn starchor sweet-potato starch; and lubricants, such as magnesium stearate,calcium stearate, sodium stearylfumaric acid or polyethyleneglycol wax.In the case of capsule formulation, liquid carriers including fatty oilmay be further included, in addition to the above materials.

Pharmaceutical preparations for parenteral administration comprisesterile aqueous solution, water-insoluble solvent, suspension, emulsion,and lyophilized agent. As the water-insoluble solvent and suspension,use may be made of vegetable oil such as propylene glycol, polyethyleneglycol, olive oil, and injection ester, such as ethyl oleate.

In typical medical substances, effective doses of the compound of theformula I according to the present invention may range from 0.2 to 2.0mg/kg, and they can be administered in a single dose or in divided dailydoses. However, it should be understood by anyone skilled in the artthat the amount of the active ingredient actually administered ought tobe determined in light of various relevant factors includingconstitutional peculiarity and body weight of the individual subject,kinds and severity of diseases, properties of dosage form, properties ofmedicinal administration, and administration period or interval.

A better understanding of the present invention may be obtained in lightof the following examples which are set forth to illustrate, but are notto be construed to limit the present invention.

EXAMPLE 1 Preparation of 6-O-(4-methoxyaniline)acetyl Fumagillol Step 1:(Acylation) Preparation of 6-O-chloroacetyl Fumagillol

Fumagillol (500 mg) in dichloromethane (10 ml) was added withdimethylaminopyridine (432 mg) and chloroacetyl chloride (199 mg), andstirred at room temperature for 1 hour. The reaction was vacuumconcentrated, to give the residue, which was then purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=1:4), yielding 270 mg ofthe title compound as a light yellow oil.

¹H-NMR (CDCl₃) δ: 5.76-5.74 (m, 1H), 5.22 (br t, 1H, J=7.3 Hz), 4.19 (s,2H), 3.71 (dd, 1H, J=2.8, 11.1 Hz), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3Hz), 2.58 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.3 Hz), 2.41-1.81 (m, 9H),1.75 (s, 3H), 1.66 (s, 3H), 1.24 (s, 3H), 1.18-1.06 (m, 1H).

Step 2: (Substitution) Preparation of 6-O-(4-methoxyaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1,was dissolved in dimethylformamide (1 ml), to which 4-methoxyaniline(0.055 mg) was added. The mixture was further with K₂CO₃ (61.48 mg) andKI (73.84 mg) and stirred at 70° C. for 6 hours.

Thereafter, the resultant reaction was diluted with ethyl acetate (20ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml)and saturated brine (5 ml). The organic layer was separated, dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 112mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.57 (s, 2H), 5.70-5.73 (m, 1H), 5.19 (br t, 1H, J=7.3Hz), 4.21 (s, 2H), 3.86 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.45 (s,3H), 3.01 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2Hz), 2.43-1.83 (m, 6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H) 1.19-1.03(m, 1H).

EXAMPLE 2 Preparation of 6-O-(3,4,5-trimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (166 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,4,5-trimethoxyaniline (0.079 mg) was added. Then, this mixture wasfurther added with K₂CO₃ (63.78 mg) and KI (76.61 mg), and stirred at70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was separated, and dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 136mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.54 (s, 2H), 5.73-5.73 (m, 1H), 5.21 (br t, 1H, J=7.3Hz), 4.21 (s, 2H), 3.89 (s, 9H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.44 (s,3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H) 1.15-1.04(m, 1H).

EXAMPLE 3 Preparation of 6-O-(2,4-dimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (168 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which2,4-dimethoxyaniline (0.072 mg) was added. Then, the mixture was furtheradded with K₂CO₃ (64.54 mg) and KI (77.52 mg) and stirred at 70° C. for6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was separated, dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 140mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.57-6.48 (m, 3H), 5.73-5.71 (m, 1H), 5.24 (br t, 1H,J=7.2 Hz), 4.23 (s, 2H), 3.91 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.0 Hz),3.49 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d,1H, J=4.3 Hz), 2.43-1.83 (m, 6H), 1.77 (s, 3H) 1.66 (s, 3H) 1.24 (s, 3H)1.15-1.01 (m, 1H).

EXAMPLE 4 Preparation of 6-O-(3,4-dimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (164 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,4-dimethoxyaniline (0.07 mg) was added. Then, the mixture was addedwith K₂CO₃ (63.01 mg) and KI (75.68 mg), and stirred at 70° C. for 6hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 132mg of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 6.54-6.47 (m, 3H), 5.73-5.69 (m, 1H), 5.21 (br t, 1H,J=7.2 Hz), 4.25 (s, 2H), 3.86 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.51 (s, 3H), 3.03 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d,1H, J=4.2 Hz), 2.41-1.81 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.26 (s, 3H)1.18-1.02 (m, 1H).

EXAMPLE 5 Preparation of 6-O-(3,4-dimethoxy-6-nitroaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (154 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,4-dimethoxy-6-nitroaniline (0.085 mg). Then, the mixture was addedwith K₂CO₃ (59.18 mg) and KI (71.08 mg) and stirred at 70° C. for 6hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 161mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.73-6.66 (m, 2H), 5.75-5.71 (m, 1H), 5.23 (br t, 1H,J=7.2 Hz), 4.27 (s, 2H), 3.93 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.49 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d,1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.64 (s, 3H) 1.25 (s, 3H)1.18-1.03 (m, 1H).

EXAMPLE 6 Preparation of 6-O-(3,4-dimethoxy-6-cyanoaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,4-dimethoxy-6-cyanoaniline (0.079 mg) was added. The mixture wasfurther added with K₂CO₃ (61.48 mg) and KI (73.84 mg), and stirred at70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was vacuum concentrated togive the residue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 128 mg of the title compoundas a white solid.

¹H-NMR (CDCl₃) δ: 6.77-6.64 (m, 2H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H,J=7.2 Hz), 4.26 (s, 2H), 3.90 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.51 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d,1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H)1.19-1.04 (m, 1H).

EXAMPLE 7 Preparation of 6-O-(4-allyloxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (165 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which4-allyloxyaniline (0.085 mg) was added. The mixture was further addedwith K₂CO₃ (63.40 mg) and KI (76.14 mg) and stirred at 70° C. for 7hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 151 mgof the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 6.58-6.54 (m, 2H), 6.32-6.29 (m, 2H), 5.87-5.85 (m,1H), 5.73-5.70 (m, 1H), 5.41-5.35 (m, 2H), 5.21 (br t, 1H, J=7.2 Hz),4.61 (d, 2H, J=7.4 Hz), 4.26 (s, 2H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.51 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d,1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H)1.19-1.04 (m, 1H).

EXAMPLE 8 Preparation of 6-O-(4-(2-acetoxyethoxy)aniline)acetylFumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which4-(2-acetoxyethoxy)aniline (0.08 mg) was added. Then, the mixture wasfurther added with K₂CO₃ (61.48 mg) and KI (73.84 mg) and stirred at 70°C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 153 mgof the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 6.54-6.52 (m, 2H), 6.38-6.34 (m, 2H), 5.73-5.70 (m,1H), 5.21 (br t, 1H, J=7.2 Hz), 4.52 (t, 2H, J=7.0 Hz), 4.29 (t, 2H,J=7.0 Hz), 4.24 (s, 2H), 3.73 (dd, 1H, J=2.9, 11.1 Hz), 3.53 (s, 3H),3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.3 Hz),2.45-1.82 (m, 6H), 2.02 (s, 3H), 1.79 (s, 3H) 1.65 (s, 3H) 1.24 (s, 3H)1.17-1.02 (m, 1H).

EXAMPLE 9 Preparation of 6-O-(3-cyano-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (150 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3-cyano-4-methoxyaniline (0.062 mg) was added. Then, the mixture wasfurther added with K₂CO₃ (57.64 mg) and KI (69.22 mg) and stirred at 70°C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was vacuum concentrated togive the residue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 124 mg of the title compoundas a white solid.

¹H-NMR (CDCl₃) δ: 6.77-6.64 (m, 3H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H,J=7.2 Hz), 4.25 (s, 2H), 3.92 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.54 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.53 (d,1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.79 (s, 3H) 1.69 (s, 3H) 1.24 (s, 3H)1.18-1.02 (m, 1H).

EXAMPLE 10 Preparation of6-O-(3-(dimethylaminomethyl)-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (153 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3-(dimethylaminomethyl)-4-methoxyaniline (0.092 mg) was added. Then, themixture was further added with K₂CO₃ (58.79 mg) and KI (70.61 mg), andstirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 161 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.43-6.19 (m, 3H), 5.73-5.70 (m, 1H), 5.23 (br t, 1H,J=7.2 Hz), 4.23 (s, 2H), 3.93 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz),3.66 (s, 2H), 3.52 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4Hz), 2.52 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 2.26 (s, 6H), 1.78 (s,3H) 1.66 (s, 3H) 1.25 (s, 3H) 1.16-1.04 (m, 1H)

EXAMPLE 11 Preparation of 6-O-(4-(2-methylpropoxyaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (152 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which4-(2-methylpropoxy)aniline (0.07 mg) was added. This mixture was furtheradded with K₂CO₃ (58.41 mg) and KI (70.15 mg), and stirred at 70° C. for6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 123 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.59-6.55 (m, 2H), 6.37-6.33 (m, 2H), 5.74-5.71 (m,1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91 (d, 2H, J=6.5 Hz),3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.03 (d, 1H, J=4.1 Hz),2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 7H), 1.78(s, 3H) 1.66 (s, 3H) 1.25 (s, 3H), 1.19 (d, 6H, J=6.1 Hz), 1.15-1.01 (m,1H)

EXAMPLE 12 Preparation of 6-O-(3-isopropoxy-4-methoxyaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (161 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3-(isopropoxy)-4-methoxyaniline (0.081 mg) was added. This mixture wasadded with K₂CO₃ (61.87 mg) and KI (74.3 mg), and stirred at 70° C. for6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 151 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.43-6.11 (m, 3H), 5.73-5.70 (m, 1H), 5.23 (br t, 1H,J=7.2 Hz), 4.23 (s, 2H), 4.11 (q, 1H, J=6.7 Hz), 3.93 (s, 3H), 3.74 (dd,1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H,J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.78 (s, 3H) 1.66(s, 3H), 1.40 (d, 6H, J=6.7 Hz), 1.25 (s, 3H) 1.16-1.04 (m, 1H).

EXAMPLE 13 Preparation of 6-O-(4-(N,N-dimethylethoxy)aniline)acetylFumagillol

6-O-chloroacetyl fumagillol (154 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which4-(N,N-dimethylethoxy)aniline (0.077 mg) was added. This mixture wasfurther added with K₂CO₃ (59.18 mg) and KI (71.08 mg), and stirred at70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 158 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.61-6.57 (m, 2H), 6.39-6.35 (m, 2H), 5.74-5.70 (m,1H), 5.26 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 4.03 (t, 2H, J=6.8 Hz),3.75 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.05 (d, 1H, J=4.1 Hz),2.57 (t, 1H, J=6.4 Hz), 2.79 (t, 2H, J=6.8 Hz), 2.59 (s, 6H), 2.50 (d,1H, J=4.1 Hz), 2.45-1.80 (m, 6H), 1.77 (s, 3H) 1.65 (s, 3H) 1.26 (s,3H), 1.17-1.02 (m, 1H).

EXAMPLE 14 Preparation of 6-O-(3,5-diisopropyl-4-methoxyaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,5-diisopropyl-4-methoxyaniline (0.092 mg) was added. This mixture wasfurther added with K₂CO₃ (61.48 mg) and KI (73.84 mg), and stirred at70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The obtained filtrate wasvacuum concentrated to give the residue, which was purified by silicagel column chromatography (methanol:dichloromethane=1:10), yielding 171mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.58-6.54 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H,J=7.2 Hz), 4.23 (s, 2H), 3.91 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz),3.52 (s, 3H), 3.19 (q, 2H, J=6.3 Hz), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t,1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 6H), 1.78 (s, 3H)1.69 (s, 3H), 1.32 (d, 12H, J=6.3 Hz), 1.25 (s, 3H), 1.18-1.00 (m, 1H).

EXAMPLE 15 Preparation of 6-O-(3,5-dimethyl-4-methoxyaniline)acetylFumagillol

6-O-chloroacetyl fumagillol (155 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3,5-dimethyl-4-methoxyaniline (0.065 mg) was added. This mixture wasfurther added with K₂CO₃ (59.56 mg) and KI (71.53 mg), and stirred at70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 145 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.56-6.51 (m, 2H), 5.75-5.72 (m, 1H), 5.27 (br t, 1H,J=7.2 Hz), 4.25 (s, 2H), 3.93 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz),3.55 (s, 3H), 3.04 (d, 1H, J=4.1 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.50 (d,1H, J=4.1 Hz), 2.45-1.80 (m, 12H), 1.78 (s, 3H) 1.69 (s, 3H), 1.25 (s,3H), 1.18-1.00 (m, 1H).

EXAMPLE 16 Preparation of6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (158 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which3-isopropyl-4-ethoxy-6-methylaniline (0.101 mg) was added. This mixturewas added with K₂CO₃ (60.71 mg) and KI (72.91 mg), and stirred at 70° C.for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 166 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.54-6.51 (m, 2H), 5.75-5.72 (m, 1H), 5.27 (br t, 1H,J=7.2 Hz), 4.21 (s, 2H), 3.97 (q, 2H, J=6.2 Hz), 3.74 (dd, 1H, J=2.9,11.1 Hz), 3.52 (s, 3H), 3.14 (q, 1H, J=6.5 Hz), 3.03 (d, 1H, J=4.1 Hz),2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 9H), 1.78(s, 3H) 1.69 (s, 3H), 1.35 (t, 3H, J=6.2 Hz), 1.28 (d, 6H, J=6.5 Hz),1.25 (s, 3H), 1.18-1.00 (m, 1H).

EXAMPLE 17 Preparation of 6-O-(4-propyloxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to which4-propyloxyaniline (0.084 mg) was added. This mixture was added withK₂CO₃ (61.48 mg) and KI (73.84 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The separated organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 105 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.63-6.58 (m, 2H), 6.40-6.36 (m, 2H), 5.74-5.71 (m,1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.95 (t, 2H, J=6.8 Hz),3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.55 (s, 3H), 3.01 (d, 1H, J=4.1 Hz),2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.82 (m, 6H),1.77-1.74 (m, 5H) 1.68 (s, 3H) 1.26 (s, 3H), 1.15-1.01 (m, 4H).

EXAMPLE 18 Preparation of 6-O-(aniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (157 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), to whichaniline (0.04 mg) was added. This mixture was added with K₂CO₃ (60.33mg) and KI (72.46 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The obtained filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 118 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 7.66-7.14 (m, 5H), 5.75-5.71 (m, 1H), 5.20 (br t, 1H,J=7.3 Hz), 4.18 (s, 2H), 3.72 (dd, 1H, J=2.8, 11.1 Hz), 3.45 (s, 3H),3.00 (d, 1H, J=4.3 Hz), 2.59 (t, 1H, J=6.4 Hz), 2.58 (d, 1H, J=4.3 Hz),2.41-1.81 (m, 6H), 1.78 (s, 3H) 1.66 (s, 3H), 1.26 (s, 3H), 1.17-1.04(m, 1H).

EXAMPLES 19-38

The fumagillol derivatives represented by the formula I were prepared inthe same manner as in the above example 1, except that aromaticcompounds were changed. The results are given in Table 2, below. TABLE 2Ex. No. Fumagillol Derivative Aromatic Compound 196-O-(4-chloroaniline)acetyl fumagillol 4-chloroaniline 206-O-(4-dimethylaminoaniline)acetyl fumagillol 4-dimethylaminoaniline 216-O-(4-hydroxyaniline)acetyl fumagillol 4-hydroxyaniline 226-O-(4-aminoaniline)acetyl fumagillol 4-aminoaniline 236-O-(3,4-methylenedioxyaniline)acetyl 3,4-methylenedioxyanilinefumagillol 24 6-O-(4-nitroaniline)acetyl fumagillol 4-nitroaniline 256-0-(2,3,4-trimethoxyaniline)acetyl 2,3,4-trimethoxyaniline fumagillol26 6-0-(4-acetoxy-3,5-dimethoxyaniline)acetyl4-acetoxy-3,5-dimethoxyaniline fumagillol 276-0-(3,4-dimethoxy-4-hydroxyaniline)acetyl3,4-dimethoxy-4-hydroxyaniline fumagillol 286-O-(4-dimethylaminoethoxyaniline)acetyl 4-dimethylaminoethoxyanilinefumagillol 29 6-0-(4-ethylamino)acetyl fumagillol 4-ethylamino 306-0-(4-ethylaminoaniline)acetyl fumagillol 4-ethylaminoaniline 316-O-(3-dimethylaminomethyl-4- 3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol methoxyaniline 326-O-(4-trifluoromethylaniline)acetyl 4-trifluoromethylaniline fumagillol33 6-O-(4-acetoxyaniline)acetyl fumagillol 4-acetoxyaniline 346-O-(4-cyanoaniline)acetyl fumagillol 4-cyanoaniline 356-O-(4-hydroxyethoxyaniline)acetyl fumagillol 4-hydroxyethoxyaniline 366-O-(5-amino-2-methoxypyridine)acetyl 5-amino-2-methoxypyridinefumagillol 37 6-O-(5-methoxypyrimidine-2-amino)acetyl5-methoxypyrimidine-2-amino fumagillol 386-O-(3-methoxy-6-aminopyridazine)acetyl 3-methoxy-6-aminopyridazinefumagillol

Each of the fumagillol derivatives, obtained from the above examples 1and 2, was treated with an acid, or reacted with a salt in the presenceof an acid catalyst, to perform an oxirane ring-opening reaction.

EXAMPLE 39 Preparation of4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(4-methoxyaniline)acetyl fumagillol (100 mg), obtained from theabove example 1, was dissolved in tetrahydrofuran (10 ml), to whichchlorolithium (48 mg) and acetic acid (0.12 ml) were added. This mixturewas stirred at 30° C. for 36 hours. The resultant reaction was addedwith water (10 ml) and ethyl acetate (100 ml). The organic layer wasseparated, washed with saturated brine (10 ml), dried over anhydrousmagnesium sulfate and filtered, followed by distilling off the solventunder reduced pressure. Then, thusly obtained residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:2), to give85 mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.57 (s, 2H), 5.70-5.73 (m, 1H), 5.19 (br t, 1H, J=7.3Hz), 4.21 (s, 2H), 3.86 (3s, 9H), 3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.45(s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H,J=4.2 Hz), 2.43-1.83 (m, 6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H)1.19-1.03 (m, 1H)

EXAMPLE 40 Preparation of4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol (100 mg), obtained fromthe above example 2, in tetrahydrofuran (10 ml), was added withhydrochloric acid (0.14 ml) and stirred for 32 hours. This mixture wasadded with water (10 ml) and ethyl acetate (100 ml). The organic layerwas separated, washed with saturated brine (10 ml), dried over anhydrousmagnesium sulfate and filtered. Then, the solvent was distilled offunder reduced pressure, to give the residue, which was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:2), yielding72 mg of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 6.54 (s, 2H), 5.73-5.73 (m, 1H), 5.21 (br t, 1H, J=7.3Hz), 4.21 (s, 2H), 3.89 (3s, 9H), 3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.44(s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H,J=4.2 Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H)1.15-1.04 (m, 1H).

EXAMPLE 41 Preparation of 6-O-(ethylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith ethylamine (16 mg) and stirred at room temperature for 5 hours. Thereaction was diluted with ethyl acetate (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine(5 ml). The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was vacuum concentrated to give the residue,which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 84 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.72-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 3.67(dd, 1H, J=2.8, 11.1 Hz), 3.58-3.39 (m, 5H), 3.48 (s, 3H), 3.00 (d, 1H,J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.3 Hz), 2.50 (q, 2H,J=11.0 Hz), 2.41-1.81 (m, 9H), 1.73 (s, 3H), 1.66 (s, 3H), 1.25 (s, 3H),1.18-1.05 (m, 4H), 1.00 (t, 3H, J=11.0 Hz).

EXAMPLE 42 Preparation of 6-O-(isopropylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (134 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith isopropylamine (22 mg) and stirred at room temperature for 5 hours.The reaction was diluted with ethyl acetate (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine(5 ml). The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was vacuum concentrated to give the residue,which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 93 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.71 (m, 1H), 5.19 (br t, 1H, J=7.2 Hz), 3.65(dd, 1H, J=2.8, 11.1 Hz), 3.56-3.37 (m, 5H), 3.47 (s, 3H), 3.02 (d, 1H,J=4.2 Hz), 2.59 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.2 Hz), 2.50 (q, 1H,J=11.2 Hz), 2.44-1.82 (m, 9H), 1.72 (s, 3H), 1.64 (s, 3H), 1.23 (s, 3H),1.13-1.05 (m, 7H), 1.01 (d, 1H, J=11.2 Hz).

EXAMPLE 43 Preparation of 6-O-(propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (131 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith propylamine (22 mg) and stirred at room temperature for 8 hours.The reaction was diluted with ethyl acetate (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine(5 ml). The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was vacuum concentrated to give the residue,which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 98 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.72-5.70 (m, 1H), 5.22 (br t, 1H, J=7.2 Hz), 3.65(dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H,J=4.4 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.4 Hz), 2.51 (t, 2H,J=11.0 Hz), 2.40-1.79 (m, 9H), 1.75 (s, 3H), 1.67 (s, 3H), 1.24 (s, 3H),1.20-1.05 (m, 6H).

EXAMPLE 44 Preparation of 6-O-(1-butylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (128 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 1-butylamine (26 mg) and stirred at room temperature for 5 hours.The reaction was diluted with ethyl acetate (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine(5 ml). The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was vacuum concentrated to give the residue,which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 102 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.71 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 3.66(dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H,J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz), 2.54 (d, 1H, J=4.3 Hz), 2.51 (t, 2H,J=11.0 Hz), 2.40-1.79 (m, 9H), 1.76 (s, 3H), 1.69 (s, 3H), 1.25 (s, 3H),1.21-1.00 (m, 8H).

EXAMPLE 46 Preparation of 6-O-(2-methyl-butylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 2-methyl-butylamine (32 mg) and stirred at room temperature for 7hours. The reaction was diluted with ethyl acetate (20 ml) and washedwith saturated aqueous sodium hydrogen carbonate (5 ml) and saturatedbrine (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 114 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.74-5.72 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.67(dd, 1H, J=2.8, 11.1 Hz), 3.60-3.40 (m, 5H), 3.47 (s, 3H), 3.01 (d, 1H,J=4.3 Hz), 2.56 (t, 1H, J=6.3 Hz), 2.53 (d, 1H, J=4.3 Hz), 2.50 (t, 2H,J=11.2 Hz), 2.40-1.77 (m, 9H), 1.75 (s, 3H), 1.69 (s, 3H), 1.26 (s, 3H),1.21-0.95 (m, 10H).

EXAMPLE 47 Preparation of 6-O-(2,2-dimethyl-propylamino)acetylFumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 2,2-dimethyl-propylamine (32 mg) and stirred at room temperaturefor 10 hours. The reaction was diluted with ethyl acetate (20 ml) andwashed with saturated aqueous sodium hydrogen carbonate (5 ml) andsaturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was vacuum concentrated togive the residue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 103 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.70 (m, 1H), 5.20 (br t, 1H, J=7.2 Hz), 3.67(dd, 1H, J=2.9, 11.1 Hz), 3.57-3.36 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H,J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.1 Hz), 2.45-1.80 (m,10H), 1.71 (s, 3H), 1.66 (s, 3H), 1.23 (s, 3H), 1.01 (s, 9H).

EXAMPLE 50 Preparation of 6-O-(1-ethyl-propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 1-ethyl-propylamine (32 mg) and stirred at room temperature for 6hours. The reaction was diluted with ethyl acetate (20 ml) and washedwith saturated aqueous sodium hydrogen carbonate (5 ml) and saturatedbrine (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 99 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.71 (m, 1H), 5.19 (br t, 1H, J=7.1 Hz), 3.68(dd, 1H, J=2.7, 11.1 Hz), 3.57-3.35 (m, 5H), 3.46 (s, 3H), 3.01 (d, 1H,J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.52 (t, 1H,J=11.0 Hz), 2.46-1.80 (m, 9H), 1.74 (s, 3H), 1.65 (s, 3H), 1.31-1.00 (m,14H), 1.21 (s, 3H).

EXAMPLE 54 Preparation of 6-O-(1-isopropyl-2-methyl-propylamino)acetylFumagillol

6-O-chloroacetyl fumagillol (135 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 1-isopropyl-2-methyl-propylamine (43 mg) and stirred at roomtemperature for 10 hours. The reaction was diluted with ethyl acetate(20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5ml) and saturated brine (5 ml). The organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was vacuumconcentrated to give the residue, which was purified by silica gelcolumn chromatography (methanol:dichloromethane=1:10), yielding 97 mg ofthe title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.70 (m, 1H), 5.19 (br t, 1H, J=7.0 Hz), 3.65(dd, 1H, J=2.6, 11.1 Hz), 3.56-3.37 (m, 5H), 3.47 (s, 3H), 3.01 (d, 1H,J=4.3 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.3 Hz), 2.52 (d, 1H,J=11.2 Hz), 2.47-1.81 (m, 12H), 1.73 (s, 3H), 1.67 (s, 3H), 1.25 (s,3H), 0.99 (d, 12H, J=10.8 Hz).

EXAMPLE 55 Preparation of 6-O-(3-methylbutylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (134 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 3-methylbutylamine (48 mg) and stirred at room temperature for 5hours. The reaction was diluted with ethyl acetate (20 ml) and washedwith saturated aqueous sodium hydrogen carbonate (5 ml) and saturatedbrine (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 111 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.71 (m, 1H), 5.17 (br t, 1H, J=7.0 Hz), 3.66(dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m, 5H), 3.49 (s, 3H), 3.01 (d, 1H,J=4.2 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.2 Hz), 2.54-2.52 (m,1H), 2.46-1.79 (m, 13H), 1.74 (s, 3H), 1.65 (s, 3H), 1.23 (s, 3H),1.03-0.98 (m, 13H).

EXAMPLE 56 Preparation of 6-O-(2-methyl-allylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (129 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 2-methyl-allylamine (26 mg), and stirred at room temperature for 5hours. The reaction was diluted with ethyl acetate (20 ml) and washedwith saturated aqueous sodium hydrogen carbonate (5 ml) and saturatedbrine (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 105 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.74-5.71 (m, 1H), 5.52-5.48 (m, 2H), 5.21 (br t, 1H,J=7.2 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.41 (m, 5H), 3.48 (s,3H), 3.11 (br s, 2H), 3.03 (d, 1H, J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz),2.55 (d, 1H, J=4.3 Hz), 2.40-1.77 (m, 13H), 1.79 (s, 3H), 1.74 (s, 3H),1.65 (s, 3H), 1.22 (s, 3H)

EXAMPLE 63 Preparation of 6-O-(cyclopropylamino)acetyl fumagillol

6-O-chloroacetyl fumagillol (51.4 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith cyclopropylamine (8 mg) and stirred at room temperature for 8hours. The reaction was diluted with ethyl acetate (10 ml) and washedwith saturated aqueous sodium hydrogen carbonate (3 ml) and saturatedbrine (3 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 38 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.74-5.71 (m, 1H), 5.21 (br t, 1H, J=7.0 Hz), 3.64(dd, 1H, J=2.7, 11.1 Hz), 3.57-3.39 (m, 5H), 3.48 (s, 3H), 3.00 (d, 1H,J=4.3 Hz), 2.62 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.3 Hz), 2.47-1.81 (m,7H), 1.71 (s, 3H), 1.66 (s, 3H), 1.31-1.01 (m, 5H), 1.21 (s, 3H),0.98-0.87 (m, 1H), 0.55-0.41 (m, 2H).

EXAMPLE 64 Preparation of 6-O-(cyclobutylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (50.3 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith cyclobutylamine (10 mg) and stirred at room temperature for 6hours. The reaction was diluted with ethyl acetate (10 ml) and washedwith saturated aqueous sodium hydrogen carbonate (3 ml) and saturatedbrine (3 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 40 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64(dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.46 (s, 3H), 3.02 (d, 1H,J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m,1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H),1.19 (s, 3H).

EXAMPLE 65 Preparation of 6-O-(cyclopentylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (51.0 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith cyclopentylamine (12 mg) and stirred at room temperature for 6hours. The reaction was diluted with ethyl acetate (10 ml) and washedwith saturated aqueous sodium hydrogen carbonate (3 ml) and saturatedbrine (3 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 36 mg of the title compound ascolorless oil.

¹H-NMR (CDCl₃) δ: 5.73-5.67 (m, 1H), 5.22 (br t, 1H, J=7.1 Hz), 3.62(dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m, 5H), 3.44 (s, 3H), 3.21-3.10 (m,1H), 2.99 (d, 1H, J=4.2 Hz), 2.60 (t, 1H, J=6.7 Hz), 2.55 (d, 1H, J=4.2Hz), 2.44-2.35 (m, 1H), 2.21-1.60 (m, 15H), 1.74 (s, 3H), 1.64 (s, 3H),1.56-1.43 (m, 2H), 1.39-1.31 (m, 2H), 1.22-1.01 (m, 4H), 1.20 (s, 3H).

EXAMPLE 66 Preparation of 6-O-(cyclohexylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (53.5 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith cyclohexylamine (15 mg) and stirred at room temperature for 6hours. The reaction was diluted with ethyl acetate (10 ml) and washedwith saturated aqueous sodium hydrogen carbonate (3 ml) and saturatedbrine (3 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 42 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.75-5.68 (m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 3.64(dd, 1H, J=2.8, 11.0 Hz), 3.57-3.34 (m, 6H), 3.45 (s, 3H), 3.00 (d, 1H,J=4.3 Hz), 2.61 (t, 1H, J=6.7 Hz), 2.55 (d, 1H, J=4.3 Hz), 2.46-2.33 (m,2H), 2.23-1.57 (m, 14H), 1.76 (s, 3H), 1.63 (s, 3H), 1.36-1.02 (m, 10H),1.20 (s, 3H).

EXAMPLE 67 Preparation of 6-O-(4-tert-butyl-cyclohexylamino)acetylFumagillol

6-O-chloroacetyl fumagillol (128 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 4-tert-butyl-cyclohexylamine (55 mg) and stirred at roomtemperature for 6 hours. The reaction was diluted with ethyl acetate (20ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml)and saturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was vacuum concentrated togive the residue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:10), yielding 104 mg of the title compoundas a colorless oil.

¹H-NMR (CDCl₃) δ: 5.75-5.68 (m, 1H), 5.19 (br t, 1H, J=7.4 Hz), 3.65(dd, 1H, J=2.7, 11.3 Hz), 3.56-3.35 (m, 6H), 3.46 (s, 3H), 3.03 (d, 1H,J=4.4 Hz), 2.61 (t, 1H, J=6.7 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.46-2.33 (m,2H), 2.23-1.72 (m, 10H), 1.78 (s, 3H), 1.65 (s, 3H), 1.36-1.19 (m, 4H),1.21 (s, 3H), 1.16-0.94 (m, 6H), 0.82 (s, 9H)

EXAMPLE 68 Preparation of 6-O-(2-dimethylamino-1-methylethylamino)acetylFumagillol

6-O-chloroacetyl fumagillol (132 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 2-dimethylamino-1-methylethylamine (38 mg) and stirred at roomtemperature for 6 hours. The reaction was diluted with ethyl acetate (20ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml)and saturated brine (5 ml). The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was vacuum concentrated togive the residue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:5), yielding 104 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.74-5.71 (m, 1H), 5.19 (br t, 1H, J=7.0 Hz), 3.68(dd, 1H, J=2.7, 11.1 Hz), 3.56-3.37 (m, 5H), 3.49 (s, 3H), 3.03 (d, 1H,J=4.4 Hz), 2.91-2.88 (m, 1H), 2.65 (d, 2H, J=7.8 Hz), 2.61 (t, 1H, J=6.4Hz), 2.56 (d, 1H, J=4.4 Hz), 2.50 (s, 6H), 2.45-1.76 (m, 10H), 1.74 (s,3H), 1.66 (s, 3H), 1.25 (s, 3H), 1.04 (d, 3H, J=8.1 Hz)

EXAMPLE 69 Preparation of 6-O-(2-dimethylamino-propylamino)acetylFumagillol

6-O-chloroacetyl fumagillol (126 mg), obtained from the above step 1 ofthe above example 1, was dissolved in dimethylformamide (1 ml), addedwith 2-dimethyl-propylamine (36 mg) and stirred at room temperature for7 hours. The reaction was diluted with ethyl acetate (20 ml) and washedwith saturated aqueous sodium hydrogen carbonate (5 ml) and saturatedbrine (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum concentrated to give theresidue, which was purified by silica gel column chromatography(methanol:dichloromethane=1:5), yielding 118 mg of the title compound asa colorless oil.

¹H-NMR (CDCl₃) δ: 5.75-5.72 (m, 1H), 5.20 (br t, 1H, J=7.0 Hz), 3.66(dd, 1H, J=2.8, 11.1 Hz), 3.57-3.38 (m, 5H), 3.45 (s, 3H), 3.17-3.14 (m,1H), 3.01 (d, 1H, J=4.2 Hz), 2.81 (d, 2H, J=8.4 Hz), 2.62 (t, 1H, J=6.4Hz), 2.57 (d, 1H, J=4.2 Hz), 2.47 (s, 6H), 2.44-1.78 (m, 10H), 1.73 (s,3H), 1.64 (s, 3H), 1.24 (s, 3H), 1.02 (d, 3H, J=8.6 Hz).

EXAMPLES 45, 48, 49, 51-53, 57-62 and 70-77

The fumagillol derivatives, as represented by the formula I, wereprepared in the same manner as in the above example 1, except that aminecompounds were changed. The results are presented in the following Table3. TABLE 3 Ex. No. Fumagillol Derivative Amine Compound 456-O-(sec-butylamino)acetyl fumagillol sec-butylamine 486-O-(pentylamino)acetyl fumagillol Pentylamine 496-O-(1-methyl-butylamino)acetyl 1-methyl-butylamine fumagillol 516-O-(1-methyl-pentylamino)acetyl 1-methyl-pentylamine fumagillol 526-0-(1,2-dimethylbutylamino)acetyl fumagillol 1,2-dimethylbutylamine 536-O-(1,2,2-trimethylpropylamino)acetyl fumagillol1,2,2-trimethylpropylamine 57 6-O-(4-methyl-hepta-2,4-4-methyl-hepta-2,4- dienylamino)acetyl fumagillol dienylamine 586-O-(1,5-dimethyl-4-hexenylamino)acetyl 1,5-dimethyl-4- fumagillolhexenylamine 59 6-O-(1,1-dimethyl-2-propinylamino)acetyl 1,1-dimethyl-2-fumagillol propinylamine 60 6-O-(prop-2-enylamino)acetyl fumagillolprop-2-enylamine 61 6-O-(2-bromoethylamino)acetyl fumagillol2-bromoethylamine 62 6-O-(chloroethynylamino)acetyl chloroethynylaminefumagillol 70 6-0-(2-methoxy-2-methyl- 2-methoxy-2-methyl-propylamino)acetyl fumagillol propylamine 716-O-(2-oxo-propylamino)acetyl fumagillol 2-oxo-propylamine 726-O-(1,1-dimethyl-3-oxobutylamino)acetyl 1,1-dimethyl-3- fumagilloloxobutylamino 73 6-O-(ethyl-2-aminoacetate)acetyl ethyl-2-aminoacetatefumagillol 74 6-O-(alaninemethylesteramino)acetylAlaninemethylesteramine fumagillol 75 6-O-(methyl-2-amino-3,3-methyl-2-amino-3,3- dimethylbutanoate)acetyl fumagilloldimethylbutanoate 76 6-O-(allylglycinemethylester)acetylAllylglycinemethylester fumagillol 776-O-(2,2-dimethoxyethylamino)acetyl 2,2-dimethoxyethylamine fumagillol

Each of the fumagillol derivatives obtained from the above examples 63and 64 was treated with the acid, or reacted with the salt in thepresence of the acid catalyst, to perform the oxirane ring-openingreaction.

EXAMPLE 78 Preparation of4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(cyclopropylamino)acetyl fumagillol (100 mg), obtained from theabove example 63, in tetrahydrofuran (10 ml), was added withhydrochloric acid (0.14 ml) and stirred for 32 hours. The reaction wasadded with water (10 ml) and ethyl acetate (100 ml). The organic layerwas separated, washed with saturated brine (10 ml), dried over anhydrousmagnesium sulfate and filtered. Then, the solvent was distilled offunder reduced pressure to give the residue, which was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:2), yielding 54 mgof the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64(dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.49 (s, 3H), 3.02 (d, 1H,J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m,1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H),1.19 (s, 3H)

EXAMPLE 79 Preparation of4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(cyclobutylamino)acetyl fumagillol (100 mg), obtained from the aboveexample 64, in tetrahydrofuran (10 ml) was added with chlorolithium (48mg) and acetic acid (0.12 ml), and stirred at 30° C. for 36 hours. Thereaction was added with water (10 ml) and ethyl acetate (100 ml). Theorganic layer was separated, washed with saturated brine (10 ml), driedover anhydrous magnesium sulfate and filtered. Then, the solvent wasdistilled off under reduced pressure to give the residue, which waspurified by silica gel column chromatography (ethylacetate:n-hexane=1:2), yielding 49 mg of the title compound as a whitesolid.

¹H-NMR (CDCl₃) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64(dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.46 (s, 3H), 3.02 (d, 1H,J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m,1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H),1.19 (s, 3H)

PREPARATION EXAMPLE 1 Preparation of Tablet

A tablet containing the fumagillol compound of the present invention asan effective ingredient was prepared according to the followingprocesses.

The compound of the above example 1 was sieved, mixed with lactose,starch and pregelatinized corn starch. To the mixture, purified waterwas added in a suitable volume. The paste was granulated, dried, mixedwith magnesium stearate, and then compressed, to obtain the tablet.

Such a tablet comprises the following components: Compound of example 1 5.0 mg Lactose BP 150.0 mg  Starch BP 30.0 mg Pregelatinized cornstarch BP 15.0 mg Magnesium stearate  1.0 mg

PREPARATION EXAMPLE 2 Preparation of Capsule

A capsule containing the fumagillol compound of the present invention asthe effective ingredient was prepared as follows.

The compound of the example 1 was mixed with a predetermined amount of avehicle and magnesium state. Thusly obtained mixture was filled in agelatin capsule.

Such a capsule comprises the following components: Compound of theexample 1 5.0 mg Starch 1500 100.0 mg  Magnesium sterate BP 1.0 mg

PREPARATION EXAMPLE 3 Preparation of Injection

An injection containing the fumagillol compound of the present inventionas the effective ingredient was prepared as follows.

The compound of the example 1 was dissolved in a suitable volume ofsaline for injection BP. The pH of the resultant solution was controlledwith dilute hydrochloric acid BP to be 3.5, and then the solution volumewas controlled with saline for injection BP. The solution was filled in5 ml type 1 ampule made of transparent glass, and the top of ampule wasfused for sealing. The solution contained in the ampule was autoclavedat 120° C. for at least 15 minutes to be sterilized, giving theinjection.

Such an injection comprises the following components: Compound ofexample 1 100 μg/ml Dilute hydrochloric acid BP to be pH 3.5 Saline forinjection BP maximal 1 ml

EXPERIMENTAL EXAMPLE 1 Inhibitory Effect of Fumagillol Derivative onCell Growth

Using the HUVECs (human umbilical vein endothelial), the effect of thefumagillol derivative of the present invention on cell growth wasevaluated.

The HUVECs were added to M199 medium supplemented with 20% FBS (fetalbovine serum), 100 U/ml penicillin, 100 μg/ml streptomycin, 1.5 g/Lsodium bicarbonate, 0.1 mg/ml endothelial cell growth supplement (Sigma)and 0.1 mg/ml heparin (Sigma), after which the cells were incubated inan incubator at 37° C. under 5% CO₂. Cells were subcultured a maximum of8 times before being discarded.

In order to evaluate inhibitory activity of the fumagillin derivative ongrowth of HUVECs, the inventive compound was dissolved in DMSO and itsconcentration was adjusted from 10 mM to 1 mM. Cells were aliquotted to96 well plates at a density of 2×10³ cells per well and incubated forabout 12-24 hours to be properly attached to the plate. Thereafter, themedium was replaced with new medium. The cells were treated with thecompound obtained from each of the above examples at variousconcentration ranges of from 10 μM to 0.001 μM, and cultured for 2-3days, followed by removing 100 μl of the medium from each well.

Colorimetry was performed to determine the extent of cell growth. Thecells on each plate was added with 20 μl of aqueous one solution andthen incubated at 37° C. under 5% CO₂ for 2 hours. Using a 96-well platereader, absorption was measured at 490 nm. The results are given inTable 4, below.

As such, a conventional TNP-470 having angiogenesis inhibitory effectwas used as a control. TABLE 4 Compound IC₅₀ (η g/ml) TNP-470 29 Ex. 10.0071 Ex. 2 0.15 Ex. 3 0.09 Ex. 4 0.08 Ex. 5 142 Ex. 6 19 Ex. 7 21 Ex.8 42 Ex. 9 0.63 Ex. 10 0.06 Ex. 11 0.08 Ex. 12 0.07 Ex. 13 0.016 Ex. 1414 Ex. 15 0.06 Ex. 16 0.17 Ex. 17 0.61 Ex. 18 17 Ex. 19 174 Ex. 20 162Ex. 21 185 Ex. 22 179 Ex. 23 0.24 Ex. 24 181 Ex. 25 0.31 Ex. 26 179 Ex.27 88 Ex. 28 102 Ex. 29 178 Ex. 30 0.09 Ex. 31 0.06 Ex. 32 128 Ex. 33109 Ex. 34 98 Ex. 35 116 Ex. 36 0.021 Ex. 37 0.017 Ex. 38 0.019 Ex. 390.019 Ex. 40 0.18 Ex. 41 20 Ex. 42 12 Ex. 43 2400 Ex. 44 3200 Ex. 45 370Ex. 46 2600 Ex. 47 16 Ex. 48 3000 Ex. 49 44 Ex. 50 24 Ex. 51 32000 Ex.52 290 Ex. 53 162 Ex. 54 11 Ex. 55 17 Ex. 56 28 Ex. 57 420 Ex. 58 415Ex. 59 174 Ex. 60 185 Ex. 61 2800 Ex. 62 340 Ex. 63 0.008 Ex. 64 0.07Ex. 65 250 Ex. 66 0.6 Ex. 67 0.06 Ex. 68 240 Ex. 69 260 Ex. 70 178 Ex.71 260 Ex. 72 330 Ex. 73 1200 Ex. 74 800 Ex. 75 2400 Ex. 76 1490 Ex. 77330 Ex. 78 0.014 Ex. 79 0.037 Intermediate 2000

From the above Table 4, it can be seen that the inventive compoundexhibits superior inhibitory effect on cell proliferation, compared toconventionally known fumagillin. In particular, the compound in which R₁is aromatic is superior in angiogenesis inhibitory effect to thecompound in which R₁ is aliphatic. For instance, in the case where R₁ isaromatic, 6-O-(4-methoxyaniline)acetyl fumagillol of the above example 1has excellent inhibitory effect, 2000 times greater than known TNP-470.In the case where R₁ is aliphatic, 6-O-(cyclopropylamino)acetylfumagillol and 6-O-(4-(cyclobutylamino)acetyl fumagillol of the aboveexamples 63 and 64, respectively, are 100-1000 times higher ininhibitory effect on HUVEC, compared to TNP-470.

EXPERIMENTAL EXAMPLE 2 Acute Toxicity Test for Oral Administration ofFumagillol Derivative Using Rats

To investigate acute toxicity of the compound of the formula I, thefollowing experiment was performed.

Using 6-week-old specific pathogen-free (SPF) Sprague-Dawley rats, acutetoxicity was tested. Each of the compounds obtained from the aboveexamples was suspended in 0.5% methylcelluose solution, and orallyadministered once to every two rats constituting each group in the doseof 1 g/kg/15 ml. After administration, mortality, clinical symptoms andbody weight of the tested animals were observed. Hematological andblood-biochemical tests were carried out. The animals were dissected andabnormal conditions of pleural cavity and abdominal cavity were observedwith the naked eye. As the test result, there were no specificallyabnormal symptoms in any of the tested animals and no mortality. Inaddition, toxicity indicators were not observed in the body weight,hematological and blood-biochemical tests, or by dissection.

The present compounds did not show toxicity up to the amounts of 2 g/kgfor all rats, and the minimal lethal dose (LD₅₀) of each compound incase of oral administration was 2 g/kg or more, thus the presentcompound was evaluated as a safe compound.

EXPERIMENTAL EXAMPLE 3

Eight-week-old athymic Nu/Nu mice (Charles River Laboratories,Wilmington, Mass.) were inoculated with SNU-398 human hepatoma cells.The cells were reconstituted at 6×10⁶ cells/ml in 20% saline and 80%phenol red-free Matrigel. Cells (0.25 ml; 1.5 million cells) wereinjected subcutaneously in the left upper abdominal quadrant. Afterpostimmunization day 9, nude mice bearing a tumor of approximately 180mm² were subcutaneously administered MetAP2 inhibitors (50 mg/kg; n=5per each inhibitor) twice daily and an equivalent volume of vehicle wasadministered to control mice (n=5). Tumor measurements were made usingVernier calipers and tumor volumes were calculated using the ellipsoidformula: length×width×height×0.52.

The present compounds showed that significant suppression of tumorgrowth was observed compared with that of mice treated with vehiclealone (FIG. 1). The size of tumor cells was significantly different inxenografted nude mice treated with buffer alone or treated with Ex. 1and Ex. 64 (See series of photographs of FIG. 2). Furthermore, the tumorsuppressive efficacies of Ex. 1, Ex. 11, Ex. 63 and Ex. 64 were superiorto that of TNP-470. This group of MetAP2 inhibitors may thereforeprovide a novel hepatoma therapeutic regime (FIG. 1).

INDUSTRIAL APPLICABILITY

As described hereinbefore, the compound of the formula I of the presentinvention is advantageous in light of excellent angiogenesis inhibitoryeffect and low toxicity, and is usefully applicable as an angiogenesisinhibitory agent. As well, the inventive compound can inhibit cancermetastasis and treat cancer, rheumatic arthritis, psoriasis and diabeticretinopathy, which are associated with angiogenesis regarded as apathogenic phenomenon.

The present invention has been described in an illustrative manner, andit is to be understood that the terminology used is intended to be inthe nature of description rather than of limitation. Many modificationsand variations of the present invention are possible in light of theabove teachings. Therefore, it is to be understood that within the scopeof the appended claims, the invention may be practiced otherwise than asspecifically described.

1. A method for inhibiting angiogenesis comprising administering to asubject in need of treatment, a fumagillol derivative represented by thefollowing formula I or a pharmaceutically acceptable salt thereof.

wherein, X is —OH and Y is halogen, or X and Y are linked together toform an oxirane ring, B represents —(C═O)— or —CH₂—, R₁ representshydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄ thioalkyl; acetamido;acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino; C₁-C₆ alkylamino;C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; C₁-C₄ alkyloxycarboxylic acid,or

in which R₂, R₃, R₄, R₅ and R₆, which are the same or different, eachrepresents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄ thioalkyl;acetamido; acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino;C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; or C₁-C₄alkyloxycarboxylic acid; or, R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ andR₆, are linked together to form a C₁-C₃ alkylene dioxy ring, and Z₁, Z₂,Z₃, Z₄ and Z₅ each represent carbon or nitrogen.
 2. The method accordingto claim 1, wherein X and Y of the fumagillol derivative are linkedtogether to form the oxirane ring, and B of the fumagillol derivative is—(C═O)—.
 3. The method according to claim 1, wherein X and Y of thefumagillol derivative are linked together to form the oxirane ring, B ofthe fumagillol derivative is —(C═O)—, R₁ of the fumagillol derivative ishydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido; acetoxy; C₁-C₆alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl;C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄dialkylaminoalkoxy; amino; C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄hydroxyalkyl; C₁-C₄ alkyloxycarboxylic acid; or R₂, R₃, R₄, R₅ and R₆ ofthe fumagillol derivative, which are the same or different, eachrepresents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido;acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino; C₁-C₆ alkylamino;C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; or C₁-C₄ alkyloxycarboxylicacid; or R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ and R₆ of the fumagillolderivative are linked together to form the C₁-C₃ alkylene dioxy ring;and Z₁, Z₂, Z₃, Z₄ and Z₅ each represent carbon or nitrogen.
 4. Themethod according to claim 1, wherein X and Y of the fumagillolderivative are linked together to form the oxirane ring, B of thefumagillol derivative is —(C═O)— R₁ of the fumagillol derivative isselected from the group consisting of hydrogen; hydroxy; methyl;chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy;acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy;dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro;acetoxy; trifluoromethyl; and hydroxyethoxy; R₂, R₃, R₄, R₅ and R₆ ofthe fumagillol derivative is independently selected from the groupconsisting of hydrogen; hydroxy; methyl; chlorine; methoxy;methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino;dimethylaminomethyl; methylpropoxy; dimethylethoxy;3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy;dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy;trifluoromethyl; and hydroxyethoxy; and Z₁, Z₂, Z₃ Z₄ and Z₅ eachrepresent carbon or nitrogen.
 5. The method according to claim 1,wherein the fumagillol derivative is selected from the group consistingof: 1) 6-O-(4-methoxyaniline)acetyl fumagillol; 2)6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; 3)6-O-(2,4-dimethoxyaniline)acetyl fumagillol; 4)6-O-(3,4-dimethoxyaniline)acetyl fumagillol; 5)6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol; 6)6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol; 7)6-O-(4-allyloxyaniline)acetyl fumagillol; 8)6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol; 9)6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol; 10)6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol; 11)6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol; 12)6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol; 13)6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; 14)6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol; 15)6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol; 16)6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol; 17)6-O-(4-propyloxyaniline)acetyl fumagillol; 18) 6-O-(aniline)acetylfumagillol; 19) 6-O-(4-chloroaniline)acetyl fumagillol; 20)6-O-(4-dimethylaminoaniline)acetyl fumagillol; 21)6-O-(4-hydroxyaniline)acetyl fumagillol; 22) 6-O-(4-aminoaniline)acetylfumagillol; 23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol; 24)6-O-(4-nitroaniline)acetyl fumagillol; 25)6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol; 26)6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol; 27)6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol; 28)6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol; 29)6-O-(4-ethylaminoaniline)acetyl fumagillol; 30)6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol; 31)6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol; 32)6-O-(4-trifluoromethylaniline)acetyl fumagillol; 33) 6-O-(4-acetoxyaniline)acetyl fumagillol; 34) 6-O-(4-cyanoaniline)acetyl fumagillol;35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol; 36)6-O-(5-amino-2-methoxypyridine)acetyl fumagillol; 37)6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol; 38)6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol; 39)4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;40)4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;41) 6-O-(ethylamino)acetyl fumagillol; 42) 6-O-(isopropyl amino)acetylfumagillol; 43) 6-O-(1-propyl amino)acetyl fumagillol; 44) 6-O-(1-butylamino)acetyl fumagillol; 45) 6-O-(sec-butyl amino)acetyl fumagillol; 46)6-O-(2-methyl-butylamino)acetyl fumagillol; 47) 6-O-(t-butylamino)acetyl fumagillol; 48) 6-O-(pentyl amino)acetyl fumagillol; 49)6-O-(1-methyl-butyl amino)acetyl fumagillol; 50) 6-O-(1-ethyl-propylamino)acetyl fumagillol; 51) 6-O-(1-methyl-pentylamino)acetylfumagillol; 52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol; 53)6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol; 54)6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol; 55)6-O-(3-methylbutylamino)acetyl fumagillol; 56)6-O-(2-methylallylamino)acetyl fumagillol; 57)6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol; 58)6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol; 59)6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol; 60)6-O-(prop-2-enylamino)acetyl fumagillol; 61)6-O-(2-bromo-ethylamino)acetyl fumagillol; 62)6-O-(chloroethynylamino)acetyl fumagillol; 63)6-O-(cyclopropylamino)acetyl fumagillol; 64) 6-O-(cyclobutylamino)acetylfumagillol; 65) 6-O-(cyclopentylamino)acetyl fumagillol; 66)6-O-(cyclohexylamino)acetyl fumagillol; 67)6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol; 68)6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol; 69)6-O-(2-dimethylamino-propylamino)acetyl fumagillol; 70)6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol; 71)6-O-(2-oxo-propylamine)acetyl fumagillol; 72)6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol; 73)6-O-(ethyl-2-aminoacetate)acetyl fumagillol; 74)6-O-(alanine-methylesteramino)acetyl fumagillol; 75)6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol; 76)6-O-(allylglycine-methylester)acetyl fumagillol; 77)6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol; 78)4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;and 79)4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.6. A method for treating cancer, rheumatoid arthritis, psoriasis ordiabetic retinopathy, or for inhibiting cancer metastasis, comprisingadministering to a subject in need of treatment, a fumagillol derivativerepresented by the following formula I or a pharmaceutically acceptablesalt thereof.

wherein, X is —OH and Y is halogen, or X and Y are linked together toform an oxirane ring, B represents —(C═O)— or —CH₂—, R₁ representshydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄ thioalkyl; acetamido;acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; c₁-C₄alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino; C₁-C₆ alkylamino;C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; C₁-C₄ alkyloxycarboxylic acid,or

in which R₂, R₃, R₄, R₅ and R₆, which are the same or different, eachrepresents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; C₁-C₄ thioalkyl;acetamido; acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino;C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; or C₁-C₄alkyloxycarboxylic acid; or, R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ andR₆, are linked together to form a C₁-C₃ alkylene dioxy ring, and Z₁, Z₂,Z₃, Z₄ and Z₅ each represent carbon or nitrogen.
 7. The method accordingto claim 6, wherein X and Y of the fumagillol derivative are linkedtogether to form the oxirane ring, and B of the fumagillol derivative is—(C═O)—.
 8. The method according to claim 6, wherein X and Y of thefumagillol derivative are linked together to form the oxirane ring, B ofthe fumagillol derivative is —(C═O)—, R₁ of the fumagillol derivative ishydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido; acetoxy; C₁-C₆alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄ dialkylaminoalkyl;C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄ alkylaminoalkoxy; C₁-C₄dialkylaminoalkoxy; amino; C₁-C₆ alkylamino; C₁-C₄ dialkylamino; C₁-C₄hydroxyalkyl; C₁-C₄ alkyloxycarboxylic acid; or R₂, R₃, R₄, R₅ and R₆ ofthe fumagillol derivative, which are the same or different, eachrepresents hydrogen; hydroxy; —CN; —NO₂; —CF₃; formyl; acetamido;acetoxy; C₁-C₆ alkyl; C₁-C₄ aminoalkyl; C₁-C₄ alkylaminoalkyl; C₁-C₄dialkylaminoalkyl; C₁-C₆ alkoxy; C₁-C₆ aminoalkoxy; C₁-C₄alkylaminoalkoxy; C₁-C₄ dialkylaminoalkoxy; amino; C₁-C₆ alkylamino;C₁-C₄ dialkylamino; C₁-C₄ hydroxyalkyl; or C₁-C₄ alkyloxycarboxylicacid; or R₂ and R₃, R₃ and R₄, R₄ and R₅, or R₅ and R₆ of the fumagillolderivative are linked together to form the C₁-C₃ alkylene dioxy ring;and Z₁, Z₂, Z₃, Z₄ and Z₅ each represent carbon or nitrogen.
 9. Themethod according to claim 6, wherein X and Y of the fumagillolderivative are linked together to form the oxirane ring, B of thefumagillol derivative is —(C═O)— R₁ of the fumagillol derivative isselected from the group consisting of hydrogen; hydroxy; methyl;chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy;acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy;dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro;acetoxy; trifluoromethyl; and hydroxyethoxy; R₂, R₃, R₄, R₅ and R₆ ofthe fumagillol derivative is independently selected from the groupconsisting of hydrogen; hydroxy; methyl; chlorine; methoxy;ethylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino;dimethylaminomethyl; methylpropoxy; dimethylethoxy;3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy;dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy;trifluoromethyl; and hydroxyethoxy; and Z₁, Z₂, Z₃ Z₄ and Z₅ eachrepresent carbon or nitrogen.
 10. The method according to claim 6,wherein the fumagillol derivative is selected from the group consistingof: 1) 6-O-(4-methoxyaniline)acetyl fumagillol; 2)6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; 3)6-O-(2,4-dimethoxyaniline)acetyl fumagillol; 4)6-O-(3,4-dimethoxyaniline)acetyl fumagillol; 5)6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol; 6)6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol; 7)6-O-(4-allyloxyaniline)acetyl fumagillol; 8)6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol; 9)6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol; 10)6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol; 11)6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol; 12)6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol; 13)6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; 14)6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol; 15)6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol; 16)6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol; 17)6-O-(4-propyloxyaniline)acetyl fumagillol; 18) 6-O-(aniline)acetylfumagillol; 19) 6-O-(4-chloroaniline)acetyl fumagillol; 20)6-O-(4-dimethylaminoaniline)acetyl fumagillol; 21)6-O-(4-hydroxyaniline)acetyl fumagillol; 22) 6-O-(4-aminoaniline)acetylfumagillol; 23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol; 24)6-O-(4-nitroaniline)acetyl fumagillol; 25)6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol; 26)6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol; 27)6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol; 28)6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol; 29)6-O-(4-ethylaminoaniline)acetyl fumagillol; 30)6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol; 31)6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol; 32)6-O-(4-trifluoromethylaniline)acetyl fumagillol; 33) 6-O-(4-acetoxyaniline)acetyl fumagillol; 34) 6-O-(4-cyanoaniline)acetyl fumagillol;35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol; 36)6-O-(5-amino-2-methoxypyridine)acetyl fumagillol; 37)6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol; 38)6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol; 39)4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;40)4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;41) 6-O-(ethylamino)acetyl fumagillol; 42) 6-O-(isopropyl amino)acetylfumagillol; 43) 6-O-(1-propyl amino)acetyl fumagillol; 44) 6-O-(1-butylamino)acetyl fumagillol; 45) 6-O-(sec-butyl amino)acetyl fumagillol; 46)6-O-(2-methyl-butylamino)acetyl fumagillol; 47) 6-O-(t-butylamino)acetyl fumagillol; 48) 6-O-(pentyl amino)acetyl fumagillol; 49)6-O-(1-methyl-butyl amino)acetyl fumagillol; 50) 6-O-(1-ethyl-propylamino)acetyl fumagillol; 51) 6-O-(1-methyl-pentylamino)acetylfumagillol; 52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol; 53)6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol; 54)6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol; 55)6-O-(3-methylbutylamino)acetyl fumagillol; 56)6-O-(2-methylallylamino)acetyl fumagillol; 57)6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol; 58)6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol; 59)6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol; 60)6-O-(prop-2-enylamino)acetyl fumagillol; 61)6-O-(2-bromo-ethylamino)acetyl fumagillol; 62)6-O-(chloroethynylamino)acetyl fumagillol; 63)6-O-(cyclopropylamino)acetyl fumagillol; 64) 6-O-(cyclobutylamino)acetylfumagillol; 65) 6-O-(cyclopentylamino)acetyl fumagillol; 66)6-O-(cyclohexylamino)acetyl fumagillol; 67)6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol; 68)6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol; 69)6-O-(2-dimethylamino-propylamino)acetyl fumagillol; 70)6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol; 71)6-O-(2-oxo-propylamine)acetyl fumagillol; 72)6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol; 73)6-O-(ethyl-2-aminoacetate)acetyl fumagillol; 74)6-O-(alanine-methylesteramino)acetyl fumagillol; 75)6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol; 76)6-O-(allylglycine-methylester)acetyl fumagillol; 77)6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol; 78)4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;and 79)4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.11. Use of a compound of formula I in the preparation of a medicamentfor inhibiting development of a hepatoma in a patient, wherein saidcompound of formula I is as represented by the claim 1.